Association Between Suicidal Behavior and TPH1 and TPH2 Genes of Serotonergic System in Polish Affective Group

Open Access Full Text Article Annals of Depression and Anxiety A Austin Publishing Group

Research Article Association between Suicidal Behavior and TPH1 and TPH2 Genes of Serotonergic System in Polish Affective Group

Joanna Pawlak1*, Monika Dmitrzak-Weglarz1, Aleksandra Szczepankiewicz1,2, Monika Wilkosc3, Abstract Maria Skibinska1, Dorota Zaremba1, Aleksandra Suicide stayed important practical problem in psychiatry. Looking for genetic Rajewska-Rager1,4, Magdalena Labedzka1, Pawel predisposition to suicide we considered polymorphisms of TPH1 and TPH2 Kapelski1 and Joanna Hauser1 genes, a rate limiting enzyme in serotonin synthesis. We focused on affective 1Psychiatric Genetics Unit, Department of Psychiatry, patients, most vulnerable to suicide psychiatric group. In the study were included Poznan University of Medical Sciences, Poland 549 unrelated patients and 370 healthy controls. The selected polymorphisms 2Department of Molecular and Cell Biology, Poznan were genotyped using the Taq Man single-nucleotide polymorphism (SNP) University of Medical Sciences, Poland allelic discrimination method after extracting the DNA from blood sample. The 3Department of Individual Differences, University of Pearson’s chi-square (χ2) test and Fisher’s exact test were applied to test the Bydgoszcz, Poland genotypic and allelic associations. The results were divergent with respect to 4Department of Adult Psychiatry, Poznan University of the diagnosis and suicidal behavior. TPH1 gene polymorphisms rs1800532 and Medical Sciences, Poland rs1799913 revealed an association to diagnosis in group of male BP and MDD *Corresponding author: Joanna Pawlak, Laboratory patients. Also rs7933505 was associated to the diagnosis of BP type I in males. of Psychiatric Genetics, Department of Psychiatry, TPH2 polymorphisms rs1386483 and rs4448731 turn out be associated to BP University of Medical Sciences, ul. Szpitalna 27/33, 60- type II. There were genotypic associations to suicide attempts in four TPH1 SNPs 572 Poznan, Poland, Tel: +48 61 8491311; Fax: +48 61 (rs1800532, rs1799913, rs7933505, rs684302) in male group, but we found no 8480392; Email: [email protected] statistically significant associations between TPH2 polymorphisms and suicidal attempts. Our results partly confirm the role of serotonergic neurotransmission Received: August 08, 2014; Accepted: September 02, in predisposition to suicide and bipolar disorder. The serotonergic system plays 2014; Published: September 05, 2014 a great role in behavior regulation and our results support that the role may partly differ according to sex.

Keywords: Suicide; Affective disorder; TPH

Introduction hippocampus, hypothalamus and amygdala [11]. A second TPH form (TPH-2) is mainly expressed in the raphe nuclei and to a lesser Serotonin is the neurotransmitter involved in such brain functions extent in the cortex, thalamus, hippocampus, hypothalamus and as mood regulation, aggressiveness, anxiety, sex, sleeping, cognition, amygdala. A significant difference in gene expression with higher memory and learning [1]. It plays important role in inhibition TPH-1 than TPH-2 mRNA levels has been shown in the amygdala of behavior undertaken upon an impulse. Reduced serotonergic and hypothalamus, which are relevant brain areas in BP [12]. releasing into synaptic cleft in the ventral prefrontal cortex may result in weaker inhibition of acting on powerful emotions [2,3]. The role of Aim of the study was to investigate the possible association serotonergic system in etiopathogenesis of depression was postulated between suicidal behavior and selected genetic polymorphisms 40 years ago by Lapin and Oxenkrug [4] and is now very widely in a sample of patients with diagnosis of affective disorders. In the documented [5]. Moreover serotonin is main neurotransmitter present paper we analyzed intronic SNPs within the TPH1 and TPH2 associated with suicidal behavior [6-8]. Epidemiological studies have genes. It was shown that an intronic TPH2 SNP was related to gene demonstrated that suicidal behavior is, at least partially, genetically expression levels [13], so potentially may influence serotonergic determined with a pattern of transmission independent of psychiatric neurotransmission. disorders [9]. Material and Methods Serotonin (5-hydroxytryptamine, 5-HT) elicits a wide array Subjects of physiological effects by binding to several receptor subtypes, In the study were included 549 unrelated patients with bipolar including the 5-HT2 family of seven-transmembrane-spanning, affective disorder (BP) and Major Depression (MDD) (328 female, 221 G-protein-coupled receptors, which activate phospholipase C and male), aged 18-84 (mean=47.04, SD±13.97). Patients were recruited D signaling pathways. TPH is a member of the aromatic amino acid in mental health center of Department of Psychiatry and hospitalized hydroxylase family. The enzyme catalyzes the first and rate limiting at inpatient clinic, Department of Adults Psychiatry, University of step in the biosynthesis of serotonin. There are two isoforms of the Medical Sciences, Poznan. Consensus diagnosis was established by TPH, which are coding by different genes: TPH1 (11p15.3–p14) two psychiatrists using Structured Clinical Interview for DSM-IV Axis and TPH2 (12q21.1). Both isoforms are expressed in human brain I Disorders (SCID-I) [14]. Among patients 216 persons (142 females [10]. TPH-1 is expressed in such regions as frontal cortex, thalamus, and 74 males; 147 BPI, 48 BPII and 21 MDD; see supplementary

Ann Depress Anxiety - Volume 1 Issue 3 - 2014 Citation: Pawlak J, Dmitrzak-Weglarz M, Szczepankiewicz A, Wilkosc M, Skibinska M, et al. Association between ISSN : 2381-8883 | www.austinpublishinggroup.com Suicidal Behavior and TPH1 and TPH2 Genes of Serotonergic System in Polish Affective Group. Ann Depress Pawlak et al. © All rights are reserved Anxiety. 2014;1(3): 1014. Joanna Pawlak Austin Publishing Group table) had a suicide attempt in lifetime history. We excluded patients, Quanto. As regards association with the diagnosis the following who committed suicide during clinical observation period, to avoid groups: BP+MDD, BPI, BPII and MDD were compared to controls. phenotypic heterogeneity. The control group consisted of 370 subjects As regards association with the suicide behavior were compared (183 female, 187 male), aged 19-64 (mean=35.37, SD±12.24). We attempters to controls and also compared suicide attempters and non used Polish version of Mini International Neuropsychiatric Interview attempters (accordingly to suggestions of [17]). screen to exclude mental diseases in controls [15]. Attempted suicide Results was defined as self-destructive behavior with at least some intentions to end one’s life [16]. The distributions of genotypes for all analyzed polymorphisms were in Hardy–Weinberg equilibrium in patients as well as in healthy After a detailed description of study procedures informed written controls (p>0.05). Using the Bonferroni correction the significance consent was obtained from all subjects. The protocol of the study was cut-off at p<0.01 was established. approved by the Ethics Committee, Poznan University of Medical Sciences. We found genotypic association between TPH1 rs1800532 and rs1799913 polymorphisms and diagnosis of affective disorder in male Genotyping group. In pure BP type I group rs1800532, rs1799913 and rs7933505 The included polymorphisms fulfilled the following criteria: Minor genotypes were associated to the diagnosis in males. No significant Allele Frequency (MAF) above 0.10 and genotypic correlation (ρ) associations were found in BPII and MDD groups. across the genotypes of maximal 0.85. DNA was extracted from blood samples using the salting out protocol. The selected polymorphisms Among TPH2 polymorphisms we found genotypic association were genotyped using the TaqMan Single-Nucleotide Polymorphism between rs1386483 and rs4448731 and diagnosis of BP type II in (SNP) allelic discrimination method with the ABI 7900HT system. whole group. Association between rs4448731 and BPII was confirmed In the Real-Time PCR reaction the commercially available TaqMan in male subgroup. Genotyping assays (Applied Bio systems, Foster City, CA) were used. In terms of allelic associations we found differences in rs1800532 Gene variants included in the study are depicted in Table1. and rs1799913 polymorphisms between male affective patients and Computations controls. In both SNPs G allele was significantly more frequent in Statistical analyses were performed using Statistical 8.0 package patients (rs1800532: p=0.0049, OR: 0.6463, CI: 0.4789-0.8722 and (STATSOFT, Poland). The concordance of genotypes with Hardy- rs1799913: p=0.0049, OR: 0.6463, CI: 0.4789-0.8722). There were no Weinberg equilibrium was assessed using “Utility Programs for other significant allelic associations to the diagnosis. Analysis of Genetic Linkage”. The Pearson’s chi-square (χ2) test and Significant associations between diagnosis of affective disorder Fisher’s exact test were applied to test differences in the genotypic and genotype are shown in Table 2. and allelic (respectively) distribution between groups of patients and controls. Graph Pad software was used to calculate odds ratios Then the association between suicide attempts and genotype (OR) for the alleles. Power analysis was performed using Program was investigated. We found an association between TPH1 rs684302 polymorphism and suicidal attempts in comparison of suicide Supplementary Table: Gender, diagnosis and suicide attempters’ numbers. attempters vs. controls (Table 3), but it was not statistically significant BPI BPII MDD when we compared suicide attempters to non attempters. More Male (N of attempters/ total N) 57 / 173 13 / 33 4 / 15 differences were found between suicide attempters and controls in Female (N of attempters/ total N) 90 / 214 35 / 68 17 / 46 male group. There were genotypic associations to suicide attempts in Table 1: Gene variants included in the study. four TPH1 SNPs (rs1800532, rs1799913, rs7933505, rs684302). There Gene Polymorphism rs # chromosome position MAF TaqMan probe Type

TPH1 A218C C>A rs1800532 11p15.3-p14 18047816 0.39 (A) C_8940793_10 Intronic

A779C C>A rs1799913 18047255 0.45 (T) C_2645661_10 Intronic

T>G rs211105 18055304 0.32 (G) C_2645667_10 Intronic

G>A rs7933505 18045987 0.40 (A) C_2645659_10 Intronic

C>T rs684302 18060353 0.46 (T) C___2298453_20 Intronic

TPH2 G>A rs1386483 12q21.1 72412494 0.28 (A) C_8872255_10 Intronic

T>G rs1843809 72348698 0.13 (G) C_11479729_10 Intronic

C>T rs1386493 72355179 0.13 (T) C_8872331_10 Intronic

G-703T G>T rs4570625 72331923 0.20 (T) C_226207_10 5' near gene

C>T rs2171363 72360264 0.36 (T) C__15836061_10 Intronic

G>C rs1386491 72362378 0.22 (C) C___8872320_10 Intronic

T>G rs6582078 72374891 0.33 (G) C__31110916_10 Intronic

C>T rs4448731 72329106 0.43 (T) C__31110841_10

G>A rs1352250 72397784 0.38 (A) C___8376101_20 Intronic

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Table 2: Association between diagnosis of affective disorder and genotype (bolded are p values significant after correction p<0.01). Polymorphism TPH1 TPH2

Genotype rs1800532 rs1799913 rs7933505 rs684302 rs1386483 rs4448731

T 0.10086 0.11546 0.17760 0.07704 0.09891 0.95952

BP+MDD (n=536) F 0.94712 0.98048 0.99047 0.63949 0.78424 0.57426

M 0.00896 0.00896 0.01890 0.037758 0.04765 0.46350

T 0.08315 0.09513 0.19381 0.10644 0.78778 0.38417

BPI(n=375) F 0.93250 0.89860 0.82240 0.74956 0.72589 0.15605

M 0.00370 0.00370 0.00901 0.02643 0.21275 0.99857 T 0.89108 0.89404 0.85024 0.73482 0.00252 0.00988

BPII (n=100) F 0.55004 0.57800 0.61063 0.56205 0.08010 0.43682

M 0.09319 0.09319 0.13392 0.07486 0.07281 0.00890 Abbreviations: BP: Bipolar; MDD: Major Depressive Disorder (separated data are not shown, because the subgroup was smaller than n=100); BPI: Bipolar type I; BPII: Bipolar type II; T - Total; M: Males; F: Females Table 3: Association between suicide attempts and genotype in patients with affective disorders (bolded are p values significant after correction p<0.01). Polymorphism TPH1 TPH2

Genotype rs1800532 rs1799913 rs7933505 rs684302 rs1386483 rs4448731

T 0.00731 0.00878 0.01061 0.00240 0.14057 0.94290

Suicide attempt(s) in lifetime history (n=) vs controls F 0.31736 0.37078 0.42465 0.13352 0.80934 0.88043

M 0.00457 0.00457 0.00433 0.00521 0.07881 0.72165

T 0.05074 0.05074 0.03581 0.01237 0.90501 0.94323

Suicide attempters (n=) vs non attempters (n=) F 0.09190 0.09190 0.10790 0.08854 0.99036 0.79255

M 0.25277 0.25277 0.15607 0.07063 0.84659 0.98901

T 0.63543 0.65242 0.82701 0.58260 0.20953 0.96466

No suicide attempt(s) in lifetime history (n=) vs controls F 0.76197 0.69923 0.68203 0.94167 0.85351 0.46223

M 0.11970 0.11970 0.23931 0.32952 0.12345 0.49850 T: Total; M: Males; F: Females were no significant allelic associations. We found no statistically were no significant associations to MDD. We take this result with significant associations between TPH2 polymorphisms and suicidal caution (data on MDD not shown in tables) because of low number attempts both in comparison of suicide attempters vs. controls and in of MDD included. The results are also consistent to the meta-analysis comparison of suicide attempters to non attempters. Patients with no performed by Chen et al. [18]. Authors proved that polymorphism suicide attempt in lifetime history did not differ to controls in terms of TPH1 gene (rs1800532) were associated with bipolar (BP), but not of frequencies of investigated pollymorphisms. unipolar (UP) diagnosis. TPH1 and TPH2 genes were investigated in Korean population, authors included to the study 103 BP patients Discussion and 86 controls. In this (not large) group no positive findings In the associative studies devoted to the association between revealed [19]. Close scores, which we obtained for rs1800532 and TPH1 and TPH2 genes and suicidal behavior we find both positive rs1799913 associations, may result from coupling of these SNPs in and negative reports. We aimed to replicate them in well clinically the chromosome [20]. Jin Gao et al. performed a meta-analysis of characterized group. SNPs located in intron regions of genes seemed association studies on TPH2 gene and major depressive disorder [21] interesting. As regards to serotonergic system: Perroud et al. showed and concluded that there are evidence for linkage of the disease and that rs10748185 located in intron 2 of TPH2 gene, was statistically at least one of investigated SNPs (rs4570625). Our results confirm the significantly associated with mRNA levels. Authors also measured role of serotonergic system in predisposition to affective disorders, SLC6A4, TPH1, and TPH2 mRNA levels in the ventral prefrontal especially bipolar disorder. cortex suicide victims. Only TPH2 mRNA levels were found Independently of above mentioned results, we found an significantly increased in suicide completer’s vs. controls [13]. association between TPH1 rs684302 polymorphism and suicidal To find polymorphisms linked to suicide behavior, we in first attempts in comparison of suicide attempters vs. controls. After the step of the study checked if the investigated SNPs were associated to division of the studied group by gender, genotypic associations to the disease in our group. TPH1 gene polymorphisms rs1800532 and suicide attempts in four TPH1 gene’s SNPs (rs1800532, rs1799913, rs1799913 revealed an association to diagnosis in group of male BP rs7933505, rs684302) occurred in male group, but it was absent in and MDD patients. Taking into account only BP type I males also female. Again results obtained for rs1800532 and rs1799913 are very rs7933505 was associated to the diagnosis. TPH2 polymorphisms similar. Among TPH2 polymorphisms we found no associations to rs1386483 and rs4448731 turn out be associated to BP type II. There suicide attempts.

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Saetre et al. analyzed association studies on rs1800532 and our results may support that the role may partly differ according to sex. rs1799913 TPH1 gene’s polymorphisms and suicide. The group Vulnerability to numerous suicide risk factors seems be dependent on included to the meta-analysis was heterogeneous in terms of neurotransmission. It needs further investigations if it is (indirectly) psychiatric diagnosis (schizophrenia, bipolar disorder, MDD, under the influence of endocrine system. In mentioned above study alcohol abuse/dependence and borderline personality disorder). by Perroud, SLC6A4, TPH1, and TPH2 mRNA levels were different In conclusion authors found no evidence for association between between males and females, independently of suicide behavior [13]. rs1800532 and rs1799913 and suicide [17]. Our result in male group As suggested by Skogman et al. taking the role of gender into is discordant, but in total sample it is consistent. account in the assessment of suicide risk and treatment planning Maurex et al. found an association between the frequency of could improve the prevention of future suicide [35]. Improving the TPH-1 haplotype ACGCCG and low Iowa Gambling Task the effectiveness of therapeutic intervention we should be aware of performance [22]. Authors suggest the following interpretation of genetically mediated predisposition to affective disorder and suicide the results: suicidal behavior and impulsive aggression may reflect behavior supported by presented results. impairments in decision-making. Deficits in decision-making occurring in subgroup of BP patients who attempted suicide may Acknowledgment be associated with alterations in the serotonin system via TPH1 This research was supported by grant No 2011/01/B/NZ5/02795, polymorphism. financed by the Ministry of Science and Higher Education of Poland. As regards results on the association of TPH2 and suicide, we References did not replicate the results of earlier studies. Fudalej et al. found 1. Giulietti M, Vivenzio V, Piva F, Principato G, Bellantuono C, Nardi B. How TT genotype of rs1386483 associated to multiple suicide attempts much do we know about the coupling of G-proteins to serotonin receptors? and completed suicide [23]. The results of another study showed Mol Brain. 2014; 7: 49. association between rs1843809 and suicide and alcohol-related suicide 2. Malafosse A. Genetics of suicidal behavior. Am J Med Genet C Semin Med [24]. Both mentioned studies included completed suicide cases. 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